Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection

Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.     

Metoprolol reduces 'compensatory' coronary blood flow following occlusion of an adjacent branch without altering post-occlusion hyperaemia

In pentobarbitone anaesthetised, thoracotomised dogs, blood flow in one (circumflex; LCX) branch of the left coronary artery increases when an adjacent (anterior descending; LAD) branch is occluded. We show that this 'compensatory blood flow' increase results from an enhanced regional myocardial contractility, as assessed using piezoelectric crystals, and that this is to compensate for a marked decrease in segmental shortening (SS) in the region supplied by the occluded vessel. These changes in regional contractility are relatively unaffected by the intravenous administration of metoprolol whereas the LCX flow change is markedly reduced, suggesting a major contribution of coronary vascular beta(1)-adrenoceptors to such 'compensatory' flow changes.     

Ethical issues in heart failure: overview of an emerging need

Modern therapies in cardiovascular medicine aim at preventing death and improving patients' quality of life. However, cardiologists often focus on what can be done rather than what should be done, and the latter consideration may be neglected in the midst of therapeutic optimism. The life-saving success of cardiovascular treatments, combined with an aging population, has created an epidemic of heart failure, a disease that portends considerable morbidity and mortality and raises important questions about what should be done. This and the following essays in this section address the emerging need for ethical analysis of issues raised by patients with heart failure. In this overview, we discuss end-of-life care in end-stage heart failure, new therapies for heart failure, and heart failure research.     

Ruthenium(III) maltolato-nitroimidazole complexes: synthesis and biological activity

The Ru(III) metronidazole-maltolato and -ethylmaltolato complexes, trans-[RuL₂(metro)₂]CF₃SO₃ (L = ma (1a) or etma (1b)), have been synthesized and tested for potential anti-tumour activity against the human breast cancer cell line MDA-MB-435S using a so-called MTT assay in phosphate-buffered saline; ma = 3-hydroxy-2-methylpyran-4-onato, etma = 2-ethyl-3-hydroxypyran-4-onato, metro = 2-methyl-5-nitro-1H-imidazole-1-ethanol (metronidazole); MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The complexes exhibit lower IC₅₀ values than our previously reported Ru(III) tris-maltolato and -ethylmaltolato complexes [D.C. Kennedy, A. Wu, B.O. Patrick, B.R. James, Inorg. Chem. 44 (2005) 6529–6535]. An improved synthetic route to the 2-nitroimidazole EF5 (2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide) is reported, as well as a related synthesis of a 3-nitro-1,2,4-triazole derivative of EF5, triF5 (2-(3-nitro-1-H-triazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl)acetamide). The complexes [RuL₂(EF5)₂]CF₃SO₃ (4a and 4b) and [Ru(ma)₂(triF5)₂]CF₃SO₃ (5) were prepared from the [RuL₂(EtOH)₂]CF₃SO₃ complexes (3a and 3b); IC₅₀ values for 3–5 are high. Data on the uptake of Ru by the cells are also reported. The complexes were characterized generally by all or some of the following methods: elemental analyses, NMR, IR and mass spectroscopies, conductivity, and cyclic voltammetry; complexes 1a and 1b were also analyzed by X-ray crystallography.     

Vibrational characteristics of bone fracture and fracture repair: application to excised rat femur

BACKGROUND: The vibrational characteristics of any object are directly dependent on the physical properties of that object. Therefore, changing the physical properties of an object will cause the object to adopt changed natural frequencies. A fracture in a bone results in the loss of mechanical stability of the bone. This change in mechanical properties of a bone should result in a change of the resonant frequencies of that bone. A vibrational method for bone evaluation has been introduced. METHOD OF APPROACH: This method uses the radiation force of focused amplitude-modulated ultrasound to exert a vibrating force directly, and remotely, on a bone. The vibration frequency is varied in the range of interest to induce resonances in the bone. The resulting bone motion is recorded and the resonance frequencies are determined. Experiments are conducted on excised rat femurs and resonance frequencies of intact, fractured, and bonded (simulating healed) bones are measured. RESULTS: The experiments demonstrate that changes in the resonance frequency are indicative of bone fracture and healing, i.e., the fractured bone exhibits a lower resonance frequency than the intact bone, and the resonance frequency of the bonded bone approaches that of the intact bone. CONCLUSION: It is concluded that the proposed radiation force method may be used as a remote and noninvasive tool for monitoring bone fracture and healing process, and the use of focused ultrasound enables one to selectively evaluate individual bones.     

Pneumocystis oryctolagi sp. nov., an uncultured fungus causing pneumonia in rabbits at weaning: review of current knowledge, and description of a new taxon on genotypic, phylogenetic and phenotypic bases

The genus Pneumocystis comprises noncultivable, highly diversified fungal pathogens dwelling in the lungs of mammals. The genus includes numerous host-species-specific species that are able to induce severe pneumonitis, especially in severely immunocompromised hosts. Pneumocystis organisms attach specifically to type-1 epithelial alveolar cells, showing a high level of subtle and efficient adaptation to the alveolar microenvironment. Pneumocystis species show little difference at the light microscopy level but DNA sequences of Pneumocystis from humans, other primates, rodents, rabbits, insectivores and other mammals present a host-species-related marked divergence. Consistently, selective infectivity could be proven by cross-infection experiments. Furthermore, phylogeny among primate Pneumocystis species was correlated with the phylogeny of their hosts. This observation suggested that cophylogeny could explain both the current distribution of pathogens in their hosts and the speciation. Thus, molecular, ultrastructural and biological differences among organisms from different mammals strengthen the view of multiple species existing within the genus Pneumocystis. The following species were subsequently described: Pneumocystis jirovecii in humans, Pneumocystis carinii and Pneumocystis wakefieldiae in rats, and Pneumocystis murina in mice. The present work focuses on Pneumocystis oryctolagi sp. nov. from Old-World rabbits. This new species has been described on the basis of both biological and phylogenetic species concepts.     

Bactericidal and cyclooxygenase inhibitory diterpenes from Eremophila sturtii

Two serrulatane diterpenes, 3,8-dihydroxyserrulatic acid (1) and serrulatic acid (2), have been isolated from Eremophila sturtii through bioassay-guided fractionation. These compounds inhibit the inflammation pathway enzymes cyclooxygenase 1 and 2, and exhibit bactericidal activity against Staphylococcus aureus.